MYC is an oncoprotein transcription factor that features prominently in cancer. As a transcription factor, the ability of MYC to stably associate with target gene chromatin is paramount to its activity, and has been validated as an effective point of inhibition of MYC function in cancer cells. This project explores the mechanisms and significance of recruitment of MYC to chromatin by a pathway that involves the prevalent chromatin regulator WDR5. Preliminary data: (i) identify WDR5 as a direct MYC-interaction partner, (ii) define how MYC interacts with WDR5, and (iii) demonstrate that disrupting interaction with WDR5 attenuates the ability of MYC to bind chromatin and to drive tumorigenesis. Together, these data support a model in which interaction of MYC with WDR5 is required for recognition of its target genes in the context of chromatin. Importantly, the structur of the MYC-WDR5 complex reveals that the two proteins interact via an interface that is amenable to discovery of small molecule inhibitors, raising the prospect that the MYC- WDR5 nexus could open the door to novel ways to treat cancer by blocking MYC function. The goal of this project is to characterize how WDR5 recruits MYC to chromatin and to reveal the contribution of this mechanism to the basic biology and tumorigenic properties of MYC. Aim 1 will use a combination of biochemical, proteomic, and genomic approaches to delineate members of the MYC-WDR5 co-complex and define at high resolution how they associate with target gene chromatin. These studies will illuminate how MYC-WDR5 co-bound genes are selected and established, how WDR5 itself is recruited to these sites, and may very-well identify additional interaction surfaces on WDR5 that can be targeted for inhibition in cancer cells. Aim 2 will combine precision transcriptomic analyses with cell- and animal-based systems to reveal the transcriptional events that are directly controlled via the MYC-WDR5 interaction and the contribution of these events to lymphomagenesis. These studies will identify which genes depend on the MYC-WDR5 connection for regulation, define critical pathways controlled by this connection, and lay the foundation for understanding molecular events that could render cancer cells susceptible to small molecule perturbation of the MYC-WDR5 interaction. Completion of these studies will establish a new paradigm for how MYC is recruited to chromatin and develop new opportunities to discover and validate drug-like molecules that target cancer cells by inhibiting the interaction of MYC with chromatin.